The overall goal of this 5 year research plan is two-fold: (a) to characterize the molecular mechanism for[unreadable] impairment of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like[unreadable] compounds; and (b) to develop a computational model describing the biochemical pathways that regulate B[unreadable] cell differentiation and the interaction of this pathway with the aryl hydrocarbon reception (AhR). Previous[unreadable] studies have established the B cell as a sensitive cellular target for TCDD as evidenced by suppression of[unreadable] immunoglobulin (lg)M through a direct effect on B cells involving the AhR. Moreover, suppression of the IgM[unreadable] response by TCDD is mediated at the level of transcription and, in part, occurs through AhR binding to dioxin[unreadable] response elements (ORE) in regulatory domains within the Ig heavy chain (IgH) 3'a enhancer. Importantly,[unreadable] in addition to IgH suppression, the Ig kappa light chain (Igk), IgM joining chain (J chain) and X-box protein-1[unreadable] (XBP-1), which are essential for IgM assembly and secretion, are also markedly suppressed by TCDD[unreadable] suggesting the involvement of additional targets other than just the IgH 3'a enhancer. Moreover, TCDD[unreadable] alters the levels of B lymphocyte.-induced maturation protein-1 (Blimp-1), a master regulatory of B cell[unreadable] differentiation and its downstream target, Pax5, a transcriptional represser of B cell differentiation, which[unreadable] represses IgH, Igk, J chain and XBP-1. We also show that TCDD treatment of B cells: (a) altered the[unreadable] magnitude of DNA methylation and MRNA levels of DNA methylating enzymes, Dnmt3b, which putatively[unreadable] influences the expression of genes crucial to B cell differentiation, including Pax5; (b) is functionally[unreadable] antagonized by IFNg; and (c) rapidly induces the suppressor of cytokine signaling-2 (SOCS-2), a protein[unreadable] that negatively regulates signaling through cytokine receptors coupled to the JAK/STAT pathway, such as[unreadable] the IFNg receptor (IFNgR). The project objective is to test the hypothesis: Suppression of the primary[unreadable] humoral immune response by AhR agonists is mediated through changes in the B cell differentiation[unreadable] program via a mechanism that is blocked by IFNg. A computational description of the biochemical pathway[unreadable] of B cell differentiation and the direct interactions of AhR agonists on this pathway, will provide a mechanistic[unreadable] approach for predicting the effects of AhR agonists, alone and in combination as complex mixtures, on the[unreadable] pathway and on humoral immune responses.